Gastrointestinally active agents including antiulcerative H.sub.2 -antagonists are widely regarded as being useful in the treatment of ulcers and other related gastrointestinal maladies. H.sub.2 -antagonists such as famotidine are generally known to inhibit both gastric acid and pepsin secretion. See M. Miwa et al., J. Clin. Pharmacol. Ther. Toxicol., 22, 214 (1984). See also U.S. Pat. No. 4,283,408.
It is important in administering such H.sub.2 -antagonists that they be released from their dosage form quickly so that their biological uptake can be hastened and peak serum levels can be achieved relatively quickly. These desires must, however, be balanced against the need for providing an acceptable dosage form in terms of taste, convenience of use, and packaging, shipping, and handling. There are a number of dosage forms that hold a good deal of promise in administering H.sub.2 -antagonists. However, it has been difficult to date to find a vehicle which can satisfy all of many and sometimes conflicting needs and desires for such a dosage form.
One possible vehicle for administration of these gastrointestinally active agents is the effervescent tablet. Effervescence has long been known to provide some measure of taste-masking. In addition, effervescence can provide rapid disintegration of the dosage form so as to allow for generally higher bioavailability of the active agent. In this particular instance, however, what would otherwise appear upon first blush to be an ideal dosage form for H.sub.2 -antagonists is, in reality, generally unsatisfactory.
Many H.sub.2 -antagonists, while both soluble and active in acidic solutions such as those found in the stomach, are sensitive to acid exposure during storage. As effervescence generally requires the presence of an acidic and basic component, the production of a formulation including both the acidic half of an effervescent couple and an H.sub.2 -antagonist is considered undesirable due to the instability of the active ingredient in the presences of an acid. For example, Schaeffer, U.S. Pat. No. 5,102,665, acknowledges the instability of the H.sub.2 -antagonists in the presence of, for example, citric acid, which is typically used as one of the effervescent couple. Schaeffer therefore suggests that the replacement of citric acid with monoalkali metal citrate, i.e. monosodium citrate to overcome this problem. However, in some countries, such as the United States, mono- and di-sodium salts of citric acid are not generally regarded as safe.
Base coated acids are known in the art. For example, Boncey et al., U.S. Pat. No. 3,887,700 discloses aspirin compositions which are readily and completely soluble in water. The compositions consist of an aspirin core coated with a water soluble material. The coated aspirin particles may then be combined with an effervescing couple which will facilitate dissolution of the composition in water. The coating of the aspirin particles prevents the aspirin and the alkali component of the effervescent couple from reacting prematurely, thereby increasing the stability of the compositions.
Gergely et al., U.S. Pat. No. 4,678,661, discloses an effervescent composition consisting of an organic acid crystal coated with a surface layer which includes calcium carbonate. The amount of calcium carbonate disclosed is said to be approximately stoicheometric. The coating adheres to the surface of the acid crystals by means of a bonding layer which is formed by a surface reaction between the calcium carbonate coating material and the acid crystals. Effervescent tablets including these base coated acid crystals have improved stability against moisture and are useful in preparations including aspirin, ascorbic acid, gluconic acid-delta-lactone, and multivitamin mixtures. The system described in Gergely et al. can also be used to deliver incompatible substances by forming a two-layer tablet, one portion of which includes one active substance coated on the effervescent granules and the other portion of which includes the other active substance either with or without effervescent components. See also Gergely et al., U.S. Pat. No. 4,762,702. These patents do not describe the use of base coated acid effervescent particulate in combination with H.sub.2 -antagonists or other highly acid sensitive gastrointestinally active components or directly mixing said components in a single layer dosage form.
There are also other problems in addition to the problem of insuring that the acid component of the effervescent couple does not degrade or otherwise interfere with the active ingredient. First, if a traditional amount of base is used, the acid neutralization capacity of the resulting dosage form is generally above 5.0. Unfortunately, such compounds are, according to the United States Food and Drug Administration, considered antacids.
Thus the resulting H.sub.2 -antagonists containing effervescent formulations can be classified as both antacids and H.sub.2 -antagonists. As such, clearance for such a formulation would need to be acquired from the United States Food and Drug Administration by the filing of what is known as a "dual claim". A manufacturer would therefore have to prove safety and efficacy of the formulation for both the active agent and the effervescent system/antacid. This is both difficult and expensive.
It may be possible to incorporate a very small amount of an effervescent couple into a formulation so as to result in an ANC of less than 5.0. However, the resulting formulation is by no means suitable as a dosage form, let alone classifiable as an effervescent formulation in any meaningful way. Certainly, the resulting formulation would have no taste-masking ability, a very slow effervescing or disintegration time, and a generally salty taste. If, however, as the present inventors have done, an effervescent formulation including an acid sensitive gastrointestinally active agent can be formulated having an acid neutralization constant which is below 5.0, then the dual claim status can be avoided and the attendant cost and difficulty can be avoided without sacrificing performance.
In addition to problems meeting various governmental regulations, it is well known that when an H.sub.2 -antagonist, such as cimetidine, is co-administered with antacids, there is frequently a substantial reduction in the bioavailability of the H.sub.2 -antagonist. See European Pat. Application No. 0,294,193. The same antacid based decrease in bioavailability is also known to occur with the administration of famotidine and Ranitidine. See Remington's Pharmaceutical Sciences, 18th Edition, Pg. 781 published by Mack Publishing Co. One non-effervescent solution proposed in that application is at least the partial granulation of the antacid with a freely water soluble solid diluent and a rapidly swellable water-insoluble disintegrant. The ability to reduce the antacid nature of the resulting formulation would therefore also be advantageous in mitigating a reduction in the co-administration based bioavailability.
British Pat. No. 1,138,730 proposes a partial reaction of crystallized citric acid and sodium bicarbonate so as to form a mixture of mono-, di- and tri-sodium salts of 1,2,3-isopropanol tricarboxylic acid with a total free acidity of from 70% to 20%. This British patent does not disclose the product of this reaction as being a base coated acid, nor does it describe its combination with acid sensitive pharmaceutical such that the resulting stability thereof can be considered.
Alternatively, Tarral et al., U.S. Pat. No. 4,824,664, disclose the preparation of effervescent compositions including H.sub.2 -antagonist compounds. Purportedly, Tarral et al. overcome the instability of the H.sub.2 -antagonist materials in the presence of the acid component of the effervescent system by providing the citric acid used in the form of a sodium or potassium dihydrogen citrate/disodium or dipotassium hydrogen citrate couple in a weight ratio of between 8:1 and about 1:10. There is, however, no disclosure of the formation of a base coated acid. Notwithstanding, more than a stoicheometric amount of base is used in comparison to the acids used in the effervescent couple. Therefore, the resulting formulation will have an acid neutralization value higher than the desirable limit of 5.0. In another approach, European Patent No. 0,361,680 suggests incorporating of morphine into the basic component of an effervescent couple. To accomplish this, the morphine sulphate is dry mixed with sodium bicarbonate and a PVP solid binder. There is, however, no disclosure of the formation of a base coated acid.
In addition to the stability of the active ingredient, the intricacies of United States governmental regulation, and the need to minimize any reduction in the bioavailability of the active ingredient, there also remains a problem of providing an effective effervescent dosage form which is convenient to take and which can withstand the rigors of tableting, packaging, and normal shipping and handling. When acid and base components of an effervescent are used in conventional ratios, it is extremely difficult to produce a tablet without the use of substantial quantities of binder and/or the application of a significant amount of pressure.
The use of binder brings with it the introduction of unnecessary ingredients to a patient, additional cost to the manufacturer and consumer, and, inevitably, additional size to the resulting formulation. This in turn impacts the size and cost of packaging and the costs of shipping.
Alternatively, the materials can be placed under extreme pressure, (i.e. 10 tons or more), in an attempt to form a coherent tablet dosage form. However, under such circumstances it is difficult to form a tablet which will not break apart in a manner commonly referred to as "end capping" delaminate or disintegrate during subsequent tableting, packaging, shipping and handling. Even when base coated acids produced in accordance with known technique are used, these problems may still persist.